A Test of the Alzheimer Disease Framework—Did It Pass?

In 2004, the Alzheimer’s Association Workgroup proposed a revision of the criteria for Alzheimer disease (AD). They expanded on their 2018 biological definition of AD by retaining the principle that AD be defined biologically by the presence of amyloid and tau but expanded the biomarkers that would establish the diagnosis by including blood-based markers. In that context, they proposed a biological-clinical staging scheme. In this model, the clinical progression of individuals was represented by the horizontal axis and the biological spread of AD pathology on the vertical axis. The diagonal represented a complete correlation between clinical and pathologic progression if the person’s clinical state were due to AD alone. However, if the clinical symptoms were more advanced than the predicted AD biology, they would fall in the upper right part of the diagram, above the diagonal, probably due to the presence of copathologies. If the clinical presentation was less advanced than the AD biology would explain, the person would fall in the lower left part of the diagram, below the diagonal, and likely represent an individual who was resilient to AD pathology. Given this background, Brown and colleagues proposed an evaluation of the model.